Nine years after the announcement of the first functional draft of the human genome, DNA sequencing technology has advanced quite rapidly, to the point that the same task could be accomplished in minutes at approximately 100 USD per genome with the technologies that are to come this year.
|In Mexico, the National Institute|
for Genomic Medicine published
in 2009 the results of the project
Genomic Diversity in the Mexican
Population (From: INMEGEN)
At the moment, there are around 15,000 genome projects reported in the Genome Online Database (GOLD), including genomes from single organisms and also metagenomes. Among them, 3,130 have been completed and 10,541 are in process. Of these, 2,304 projects are related to metagenomes and environmental samples; finally, 1,420 genomes are related to works such as the Human Microbiome Project and GEBA (Genomic Encyclopedia of Bacteria and Archea).
Genomic sequencing and analysis are both relatively expensive activities that also demand high technical skills; consequently, the usefulness and validity of the obtained information has been questioned over the years. Some have assured that this is, indeed, the case specially regarding the genomic information provided by clinical diagnostics companies, whose activities have been termed to be a sort of "recreational genomics". However, as genome sequencing and analysis tools become more accessible, the resulting information has the potential to be of even greater value, specially regarding pharma genomics and metagenomics.
Personalized medicine and big pharma genomics
The Hoover family’s history -originally from a Mennonite community in Pennsylvania- and the genetic disease that took the life of their child and almost did the same with their daughter, is a clear example of the usefulness of counting with opportune genomic information and the technological means to process and analyze patient samples to make the best therapeutic decisions. In the case of the Hoover family, the treatment consisted of a bone marrow transplant.
Similar stories about people affected with rare diseases can be found on RareGenomics, a non-profit organization dedicated to make genomic sequencing technologies accessible to this kind of patients. One distinctive characteristics of this organization is that each patient's history is available online, allowing the information to be recognized by families that may also be in the same situation.
But what economic incentive is there in concentrating efforts in order to help a reduced sector of the general population, such as the people that are affected by unusual genetic diseases?
The answer is that, even though this sector is reduced, it is a actually a profitable market. "Orphan" drugs, also known as drugs designed to deal with rare diseases, are part of a global market that is estimated to be valued in the range of trillions of dollars, an amount greater than that of the drug market nowadays.
The use of genomic information to construct an individual profile for a patient and to determine with greater accuracy the correct therapeutic strategy, is basically what is understood when we talk about personalized medicine.
An easy way to clarify the concept is by using the example of drug metabolism.
Within traditional medicine practice, it is common to observe that the prescribed doses of some drugs only take into account physical parameters such as, for example, age and weight. However, even within individuals of the same age and weight, there are important differences in the speed in which the drug is metabolized.
Drug metabolism is affected by the variants of enzymes that are present in the body. Because of those differences, the response to a drug can be very different and it becomes necessary to rethink the prescribed dosage, as some patients may develop more severe secondary reactions, while some may not present any therapeutic effect at all even when the administered dose is the same.
Two of the most powerful tools used to associate genes and relevant clinical characteristics -like the response to certain drugs or disease susceptibility- are the Genome Wide Association Studies (GWAS) and gene candidate studies.
These studies, specially GWAS, have been subjected to criticism based on the fact that they have only been able to describe common gene variants that have low clinical impact, while high-impact genes that are rare variants in the population remain undetected. In other words, that Genome-Wide Association Studies may not identify genes with clinical importance.
This scenario, however, is about to change with the increasing accessibility to "Next Generation Sequencing" or NGS. With the possibility of sequencing complete exomes, the resolution of GWAS is expected to increase, therefore allowing the identification of rare gene variants that have greater effects over desired traits that are being researched.
The metagenomic adventure
|Sampling sites of the Sorcerer II expedition.|
From Rusch et al., (2007).
Nearly two million species have been described and cataloged worldwide, but the true total of species is estimated to be around 11 million.
The diversity of unknown organisms is a gold mine for the biotech industry, as new enzymes and metabolic pathways present in these species can potentially be of great economic and scientific value.
Nonetheless, in the case of microorganisms, in order to have direct access to these potentially valuable novel biological effectors and to describe those new species with certainty, one must be able to get an axenic culture, but only around 1% of known bacteria can be cultivated in vitro; as for the rest, the conditions needed for their growth have not yet been found.
There exists, however, another way to access the great diversity of organisms and biological effectors that remain to be discovered: the extraction and analysis of the total DNA present in an environmental sample, or in other words: to do metagenomics.
After the human genome sequencing race, Dr. Craig Venter and some of his co-workers set sail aboard Venter's own yacht, the Sorcerer II, in another more ambitious adventure: to get the genomes of all the microorganisms that they find on their way.
The Sorcerer II crew sailed across the Northern Atlantic, the Gulf of Mexico, went through the Panama Canal and got into the Pacific Ocean. Around 6 Gbp (thousands of millions of base pairs) were sequenced from 44 samples that were obtained. From this data, around 6.12 million proteins were predicted and, taking into account only the new proteins found on this trip, 3,995 protein clusters were made, of which 1,700 do not present homology to any other known proteins.
This is one of the many metagenomics studies that report the discovery of previously unknown proteins and the realization that many known proteins can be found in a wider range of organisms than what was previously thought. For example, genes related to bacterial rhodopsin, a photoreceptor that was previously thought to be present exclusively in Archea, has been found in the genomic context of some bacteria.
Researchers dedicated to the analysis of the vast amount of information from metagenomic studies have come up with new probing techniques to find genes that encode proteins with a specific function, such as antibiotic resistance, transporters and lipolytic enzymes. These methods have come to be known as functional metagenomics.
|In GOLD Genome Map and GOLD Genome Earth|
one can find a graphical representation of the places
on Earth where metagenomic samples have been taken.
Venter's team on the Sorcerer II found it very difficult to correctly assemble the different genomes obtained in their metagenomic samples. Furthermore, many of the uncommon microorganisms present in the samples were not detected at all due to their low frequency.
The use of next-generation sequencing technology provides in depth genomic information where the uncommon organisms are also represented. Recently, a research group from the University of Washington reported the isolation of individual genomes from a sample that correspond to organisms that cannot be grown in vitro, even to uncommon organisms that represent as few as 1.7% of a metagenomic sample.
From the information of individual genomes, it would be possible to infer the metabolic pathways and growth conditions for a given organism, especially the ones which remain impossible to cultivate in vitro.
With the faculty of diving into the vast world of unknown microorganisms with more certainty, an exciting era for Microbiology is just around the corner.
Translation by J. R. Aguilar Cosme